Effect of broad-based genomic sequencing on survival outcomes in advanced non-small cell lung cancer: A national cohort study, 2011-2023.

1520 Background: Use of broad-based genomic sequencing (BGS) for advanced non-small cell lung cancer (aNSCLC) is rising. While older studies have found no survival benefit with BGS, its impact on survival outcomes in the era of modern targeted therapy is unknown. Methods: In this retrospective cohort study, the 2011-2023 Flatiron Health Database—a nationally representative database of electronic health records from > 280 US cancer clinics—was queried for patients with Stage IIIB-IV NSCLC who received at least one line of systemic therapy with ≥12 months follow-up. Primary exposure was receipt of BGS vs. “Focused” biomarker testing (i.e., ALK FISH, EGFR PCR) within 90 days of first- and second-line therapy start. To address baseline confounding, we used 1:1 nearest-neighbor propensity score matching based on age at initial diagnosis, sex, self-reported race/ethnicity, histology (squamous vs. non-squamous), insurance status, smoking status, ECOG performance status, practice type (academic vs. community), stage at diagnosis, advanced diagnosis year, and practice rate of BGS. Adjusted Cox proportional hazards models compared median progression-free survival (mPFS) and median overall survival (mOS) between groups. Sensitivity analyses adjusted for biomarker status and used an instrumental variable approach. Results: Our initial unmatched cohort consisted of 35,060 patients (BGS, n = 14,192; Focused, n = 20,868; 52% female, 3.5% Asian, 9.3% Black, 3.8% Hispanic, 79% community practice). In the propensity-matched first-line therapy cohort (BGS vs. Focused, n = 10,008 in each group; all standardized mean differences < 0.1), BGS was associated with greater mPFS (6.4 vs. 6.0 months; adjusted HR [95%CI], 0.96 [0.92-1.0], p = 0.046) and mOS (16 vs. 14 months; 0.91 [0.86-0.95], p < 0.001). Sensitivity analyses were consistent with primary results. Patients receiving BGS had higher rates of ALK/EGFR positivity (18% vs. 13%) and receipt of targeted therapy (20% vs. 17%). Upon adjustment for biomarker status, however, BGS remained associated with improved OS (1.01 [0.88-0.98], p = 0.004) but not PFS (0.98 [0.94-1.03], p = 0.4). In the propensity-matched second-line therapy cohort, no associations between BGS and survival outcomes were observed. Conclusions: This is the first national analysis of survival outcomes in aNSCLC to demonstrate a survival benefit with BGS. These findings support guideline endorsement and payer coverage of BGS prior to 1 st line therapy. Median (95%CI) Univariate HR (95%CI) Adjusted HR (95%CI) First Line PFS, months Focused 6.0 (5.8-6.1) — — BGS 6.4 (6.2-6.5) 0.95 (0.91-0.99) 0.96 (0.92-1.00) OS Focused 14 (14-15) — — BGS 16 (16-17) 0.90 (0.86-0.95) 0.91 (0.86-0.95) Second Line PFS Focused 3.8 (3.5-4.1) — — BGS 4.2 (4.0-4.5) 0.91 (0.82-1.01) 0.92 (0.83-1.02) OS Focused 13 (12-14) — — BGS 12 (12-14) 1.02 (0.91-1.15) 1.01 (0.89-1.14)